Research Spotlight

Modrykamien, A. M., O. O. Hernandez, Y. Im, R. W. Walters, C. L. Schrader, L. E. Smith and B. Lima (2016). “Mechanical ventilation in patients with the acute respiratory distress syndrome and treated with extracorporeal membrane oxygenation: Impact on hospital and 30-day post-discharge survival.” Asaio j: 2016 June [Epub ahead of print].

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Mechanical ventilation support for ARDS patients involves the use of low tidal volumes and positive end-expiratory pressure. Nevertheless, the optimal ventilator strategy for ARDS patients undergoing ECMO therapy remains unknown.A retrospective analysis of a consecutive series of adult ARDS patients treated with V-V ECMO from 10/2012 to 05/2015 was performed. Mechanical ventilation, as well as demographic and clinical data were collected. We assessed the association between ventilator data and outcomes of interest. The primary outcome was hospital survival. Secondary outcome was 30-day survival post- hospital discharge.Sixty-four ARDS patients were treated with ECMO. Univariate analysis showed that plateau pressure was independently associated with hospital survival. Tidal volume, PEEP and plateau were independently associated with 30-day survival. Multivariate analysis, after controlling for covariates, revealed that a 1-unit increase in plateau pressure was associated with a 21% decrease in the odds of hospital survival (95% CI = 6.39% to 33.42%, p = .007). In regards to 30-day survival post-discharge, a 1-unit increase in plateau pressure was associated with a 14.4% decrease in the odds of achieving the aforementioned outcome (95% CI = 1.75% to 25.4%, p = .027). Also, a 1-unit increase in PEEP was associated with a 36.2% decrease in the odds of 30-day survival (95% CI = 10.8% to 54.4%, p = .009).Among ARDS patients undergoing ECMO therapy, only plateau pressure is associated with hospital survival. Plateau pressure and PEEP are both associated with 30-day survival post-hospital discharge.

Krowka, M. J., M. B. Fallon, S. M. Kawut, V. Fuhrmann, J. K. Heimbach, M. A. Ramsay, O. Sitbon and R. J. Sokol (2016). “International liver transplant society practice guidelines: Diagnosis and management of hepatopulmonary syndrome and portopulmonary hypertension.” Transplantation 100(7): 1440-1452.

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Two distinct pulmonary vascular disorders, hepatopulmonary syndrome (HPS) and portopulmonary hypertension (POPH) may occur as a consequence of hepatic parenchymal or vascular abnormalities. HPS and POPH have major clinical implications for liver transplantation. A European Respiratory Society Task Force on Pulmonary-Hepatic Disorders convened in 2002 to standardize the diagnosis and guide management of these disorders. These International Liver Transplant Society diagnostic and management guidelines are based on that task force consensus and should continue to evolve as clinical experience dictates. Based on a review of over 1000 published HPS and POPH articles identified via a MEDLINE search (1985-2015), clinical guidelines were based on, selected single care reports, small series, registries, databases, and expert opinion. The paucity of randomized, controlled trials in either of these disorders was noted. Guidelines are presented in 5 parts; I. Definitions/Diagnostic criteria; II. Hepatopulmonary syndrome; III. Portopulmonary hypertension; IV. Implications for liver transplantation; and V. Suggestions for future clinical research.

Kathania, M., P. Khare, M. Zeng, B. Cantarel, H. Zhang, H. Ueno and K. Venuprasad (2016). “Itch inhibits il-17-mediated colon inflammation and tumorigenesis by ror-gammat ubiquitination.” Nat Immunol: 2016 Jun [Epub ahead of print].

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Dysregulated expression of interleukin 17 (IL-17) in the colonic mucosa is associated with colonic inflammation and cancer. However, the cell-intrinsic molecular mechanisms by which IL-17 expression is regulated remain unclear. We found that deficiency in the ubiquitin ligase Itch led to spontaneous colitis and increased susceptibility to colon cancer. Itch deficiency in the TH17 subset of helper T cells, innate lymphoid cells and gammadelta T cells resulted in the production of elevated amounts of IL-17 in the colonic mucosa. Mechanistically, Itch bound to the transcription factor ROR-gammat and targeted ROR-gammat for ubiquitination. Inhibition or genetic inactivation of ROR-gammat attenuated IL-17 expression and reduced spontaneous colonic inflammation in Itch-/- mice. Thus, we have identified a previously unknown role for Itch in regulating IL-17-mediated colonic inflammation and carcinogenesis.

Hutson, T. E., G. R. Thoreson, R. A. Figlin and B. I. Rini (2016). “The evolution of systemic therapy in metastatic renal cell carcinoma.” Am Soc Clin Oncol Educ Book 35: 113-117.

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The treatment landscape for renal cell carcinoma (RCC) is a dynamic process that has seen considerable change in recent years. We have seen a rebirth of original breakthroughs with immune checkpoint inhibitors showing promise in patients with treatment-refractory disease. The optimal sequencing of treatments and incorporation of novel therapeutics are actively being investigated and have yet to be determined. The clinical challenges of this evolving treatment paradigm can be attributed to cost considerations, toxicity, and defining endpoints in the management of advanced RCC. As novel therapeutics emerge, finding the optimal treatment regimen for patients will have an increasing focus on patient-centered outcomes and improvement in quality of life in addition to improving survival.

Gonzalez-Hernandez, J., Y. Daoud, J. Styers, J. M. Journeycake, N. Channabasappa and H. G. Piper (2016). “Central venous thrombosis in children with intestinal failure on long-term parenteral nutrition.” J Pediatr Surg 51(5): 790-793.

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PURPOSE: Central venous thrombosis (CVT) is a serious complication of long-term central venous access for parenteral nutrition (PN) in children with intestinal failure (IF). We reviewed thse incidence of CVT and possible risk factors. METHODS: Children with IF on home PN (2010-2014) with central venous imaging were reviewed. Patient demographics, catheter characteristics and related complications, and markers of liver function were compared between children with and without CVT. Serum thrombophilia markers were reviewed for patients with CVT. RESULTS: Thirty children with central venous imaging were included. Seventeen patients had thrombosis of >/=1 central vein, and twelve had >/=2 thrombosed central veins. Patients with and without CVT had similar demographics and catheter characteristics. Patients with CVT had a significantly lower albumin level (2.76+/-0.38g/dL vs. 3.12+/-0.41g/dL, p=0.0223). The most common markers of thrombophilia in children with CVT were antithrombin, protein C and S deficiencies, and elevated factor VIII. There was a statistically significant correlation between a combined protein C and S deficiency and having >1 CVT. CONCLUSIONS: Children with IF on long-term PN are at high risk for CVT potentially owing to low levels of natural anticoagulant proteins and elevated factor FVIII activity, likely a reflection of liver insufficiency and chronic inflammation.